Neutropenia-Related Costs in Patients Treated with First-Line Chemotherapy for Advanced Non-Small Cell Lung Cancer

BACKGROUND: Neutropenia is a major adverse event often associated with chemotherapy administration. Neutropenia-related complications often lead to increased use of costly health care including inpatient and outpatient services. Monitoring and treatment of neutropenia thus place an economic burden on the health care system. OBJECTIVES: To evaluate (a) costs and medical resource use for chemotherapy-related afebrile and febrile neutropenia in an elderly population with Stage IIIB or Stage IV non-small cell lung cancer (NSCLC), and (b) costs unrelated to neutropenia and total all-cause health care costs during first-line chemotherapy. METHODS: Study patients in this retrospective database analysis were aged 65 years or older with a diagnosis of Stage IIIB or Stage IV NSCLC in the Surveillance, Epidemiology and End Results (SEER) cancer registry from 1998 through 2002. Neutropenia was identified by the presence of a primary or secondary diagnosis code for diseases of white blood cells (ICD-9-CM=288.xx) during a period of first-line chemotherapy treatment. Febrile neutropenia was defined by (a) an inpatient hospitalization with a primary or secondary diagnosis for neutropenia occurring at any time during first-line chemotherapy or (b) intravenous or intramuscular antibiotic administration occurring after the initial neutropenia diagnosis and during first-line chemotherapy. Patients with neutropenia without these events were considered to have afebrile neutropenia. Patients were followed in the SEER-Medicare database to evaluate costs (defined as all Medicare payments, primary insurer payments, and patient copayments and deductibles) and resource use associated with afebrile or febrile neutropenia while on first-line chemotherapy. If a patient switched to second-line chemotherapy, the day prior to the switch was defined as the end of first-line treatment. If a switch to second-line therapy did not occur, then first-line therapy was assumed to end 30 days following administration of the last first-line agent. Costs were summed for 2 main types of cost measures: neutropenia-related costs, defined as costs for claims with either a primary or secondary diagnosis of neutropenia, and costs unrelated to neutropenia. Costs were classified using ICD-9-CM diagnosis and procedure codes appearing on the claims, with confidence intervals [CIs] for cost measures estimated by using nonparametric bootstrapping methods. Group comparisons of patient characteristics, medical utilization, and cost study measures were made using 2-sided Pearson chi-square and t-test statistics for categorical and continuous measures, respectively. The no neutropenia group was used as the reference category for comparisons involving patient characteristic, medical utilization, and total all-cause health care cost study measures. For total neutropenia-related costs, afebrile and febrile neutropenia study groups were compared. RESULTS: Among elderly patients treated first-line for advanced NSCLC, 5,138 met inclusion criteria, of whom 1,228 (23.9%) developed afebrile (n=740, 14.4%) or febrile neutropenia (n = 488, 9.5%) while on first-line chemotherapy. Mean per patient costs for treating neutropenia during first-line chemotherapy were $12,148 (standard deviation [SD]=$15,432, 95% confidence interval [CI]=$10,915-$13,607) for patients with febrile neutropenia and $3,099 (SD=$4,541, 95% CI=$2,796-$3,431) for patients with afebrile neutropenia (P less than 0.001), with mean (SD) length of follow-up (duration of first-line chemotherapy) of 4.5 (4.8) and 5.5 (7.0) months, respectively. Expressed as a percentage of total all-cause health care costs during first-line chemotherapy, neutropenia-related costs accounted for 32.2% of total costs for patients with febrile neutropenia (mean [SD]=$37,694 [$26,078]) and 9.1% of total costs for patients with afebrile neutropenia (mean [SD]=$34,204 [$26,317]). Mean

OBJECTIVES: To evaluate (a) costs and medical resource use for chemotherapy-related afebrile and febrile neutropenia in an elderly population with Stage IIIB or Stage IV non-small cell lung cancer (NSCLC), and (b) costs unrelated to neutropenia and total all-cause health care costs during first-line chemotherapy.
METHODS: Study patients in this retrospective database analysis were aged 65 years or older with a diagnosis of Stage IIIB or Stage IV NSCLC in the Surveillance, Epidemiology and End Results (SEER) cancer registry from 1998 through 2002. Neutropenia was identified by the presence of a primary or secondary diagnosis code for diseases of white blood cells (ICD-9-CM = 288.xx) during a period of first-line chemotherapy treatment. Febrile neutropenia was defined by (a) an inpatient hospitalization with a primary or secondary diagnosis for neutropenia occurring at any time during first-line chemotherapy or (b) intravenous or intramuscular antibiotic administration occurring after the initial neutropenia diagnosis and during first-line chemotherapy. Patients with neutropenia without these events were considered to have afebrile neutropenia. Patients were followed in the SEER-Medicare database to evaluate costs (defined as all Medicare payments, primary insurer payments, and patient copayments and deductibles) and resource use associated with afebrile or febrile neutropenia while on first-line chemotherapy. If a patient switched to second-line chemotherapy, the day prior to the switch was defined as the end of first-line treatment. If a switch to second-line therapy did not occur, then first-line therapy was assumed to end 30 days following administration of the last first-line agent. Costs were summed for 2 main types of cost measures: neutropenia-related costs, defined as costs for claims with either a primary or secondary diagnosis of neutropenia, and costs unrelated to neutropenia. Costs were classified using ICD-9-CM diagnosis and procedure codes appearing on the claims, with confidence intervals [CIs] for cost measures estimated by using nonparametric bootstrapping methods. Group comparisons of patient characteristics, medical utilization, and cost study measures were made using 2-sided Pearson chi-square and t-test statistics for categorical and continuous measures, respectively. The no neutropenia group was used as the reference category for comparisons involving patient characteristic, medical utilization, and total all-cause health care cost study measures. For total neutropenia-related costs, afebrile and febrile neutropenia study groups were compared. . Mean neutropenia-related costs per patient per month (PPPM) during first-line chemotherapy were $2,700 for patients with febrile neutropenia and $563 for patients with afebrile neutropenia. PPPM costs unrelated to neutropenia for patients with afebrile neutropenia, febrile neutropenia, and no neutropenia, respectively, were $5,655, $5,677, and $6,146. In sensitivity analyses, results were highly sensitive to the definition of neutropenia (i.e., claims with primary diagnosis only vs. primary or secondary diagnosis) but insensitive to the type of chemotherapy regimen.
costs between patients with afebrile versus febrile neutropenia. Furthermore, other studies report neutropenia-related costs only for cancer patients in general, or for patients with cancer of the lung or bronchus, and have not examined outcomes or costs related to this complication in patients with advanced stage NSCLC. [13][14][15][16] The purpose of this study was to investigate and document the costs of afebrile neutropenia and febrile neutropenia in older patients with NSCLC, using data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database.

■■ Methods Data Source
Data for this study were obtained from the SEER-Medicare linked database. These data are a collaborative effort of the National Cancer Institute (NCI) and the Centers for Medicare & Medicaid Services. The NCI's SEER program is an epidemiologic surveillance system consisting of population-based tumor registries designed to track cancer incidence and mortality in the United States. As of 2008, SEER data were available for incident cases representing approximately 26% of the U.S. population. 17 SEER provides information on survival, demographics, and cancer diagnosis including site, type, histology, and stage data for up to 10 primary cancer-related diagnoses. The Medicare administrative database contains information on health care utilization and costs for hospital inpatient and outpatient care, physician services, hospice, skilled nursing facility, and home health care. Combining SEER and Medicare data allows for the comparison of costs and resource utilization by clinical status and outcomes in patients aged 65 years or older. SEER data from 1998 through 2002 and Medicare claims from 1998 through 2005 were included in this analysis. Western Institutional Review Board approved a request for a waiver of authorization for use and disclosure of protected health information for this research.

Patient Selection Criteria
The study sample included patients aged 65 years or older with a first primary diagnosis of NSCLC between 1998 and 2002. NSCLC was identified using ICD-O-2 histology codes from SEER (Appendix 1). Using the cancer incidence and stage data in SEER, patients were excluded if they had any prior history of cancer or if the stage of their cancer at diagnosis was unknown.
Additional inclusion and exclusion criteria were applied. To ensure that follow-up data on utilization and costs were complete for every patient, we included only patients completely enrolled in both Medicare Parts A and B from 1 year prior to initiation of chemotherapy until the earlier of their date of death or December 31, 2005. Those enrolled in a Medicare HMO were excluded. Using Healthcare Common Procedure Coding System (HCPCS) codes from the Medicare data, we selected patients with claims indicating receipt of specific first-line agents (Appendix 1). To ensure that study outcomes were related to incident cases of L ung cancer is the leading cause of cancer mortality in the United States. It is estimated that 159,390 deaths attributable to lung cancer are expected to occur in 2009, accounting for roughly 28% of all cancer-related deaths. 1 The majority of cases (85%-90%) are of the non-small cell lung cancer (NSCLC) type. 2 Among NSCLC patients, 55% are diagnosed with advanced (Stage IIIB or Stage IV) disease. 3 The American Cancer Society reports 5-year survival rates among patients diagnosed in Stages III and IV at only 10% and 2%, respectively. 2 Chemotherapy is a standard treatment approach for patients diagnosed with advanced NSCLC. 3 Various clinical studies have demonstrated a modest, but significant, survival benefit in patients treated with platinum-based regimens compared with supportive care alone. [4][5][6] However, patients treated with myelosuppressive chemotherapy are also at an increased risk of developing neutropenia, a common complication that can lead to serious infections and subsequent morbidity and mortality. Data from clinical trials comparing third-generation platinum regimens (gemcitabine, taxanes, or vinorelbine in combination with either cisplatin or carboplatin) show that the rates of grade 3 and 4 neutropenia and febrile neutropenia range from 30%-79% and 0.5%-16%, respectively. 7-12 Grade 3-4 neutropenia is defined as an absolute neutrophil count (ANC) of less than 1.0 x 10 9 per liter where the severity of the event is considered severe or life threatening. Febrile neutropenia occurs when a neutropenic patient has a fever (body temperature of at least 38.5° Celsius).
Neutropenia-related complications place a substantial burden on the health care system, with recent inpatient cost estimates ranging from $7,100 to $19,100 per neutropenia-related hospitalization. [13][14][15][16] Some earlier studies have focused solely on inpatient care related to febrile neutropenia 13,14 whereas more recent studies have examined both inpatient and outpatient care. 15,16 Although neutropenia-related hospitalizations are costly, they have been reported to represent approximately 60% of total neutropeniarelated costs. 16 Few studies have investigated the differences in

What this study adds
Patients with neutropenia were then subcategorized into afebrile neutropenia and febrile neutropenia. Febrile neutropenia was defined by (a) an inpatient record with either a primary or secondary ICD-9-CM diagnosis code of 288.xx occurring at any time during first-line chemotherapy or (b) an outpatient or physician services record indicating administration of intravenous or intramuscular antibiotics at any time following the initial neutropenia diagnosis but prior to the end of first-line chemotherapy. Antibiotic therapy was identified in the Medicare claims using ICD-9-CM procedure and HCPCS codes (Appendix 1). Previous studies have defined febrile neutropenia in a similar manner based on an assumption that according to standard coding practices, patients hospitalized with febrile neutropenia may not always receive a primary diagnosis code of 288.xx or codes specific to fever (780.60 or 780.61). 14,19 Patients not specifically identified as having febrile neutropenia were assumed to have afebrile neutropenia.

Cost and Utilization Outcomes
Neutropenia-related utilization measures included inpatient hospitalizations, physician visits, and receipt of granulocyte-colony stimulating factor (G-CSF) therapy. Hospitalization and physician visits related to neutropenia were identified using primary or secondary diagnosis codes of ICD-9-CM 288.xx. Therapy with G-CSF was identified in the Medicare claims using HCPCS codes (Appendix 1). Utilization unrelated to neutropenia was identified using inpatient, outpatient, and physician services claims without primary or secondary ICD-9-CM codes of 288.xx. Skilled nursing facility (SNF) and hospice care were also defined as unrelated to neutropenia. It was assumed that patients would not be placed in a SNF or hospice as a result of neutropenia.
Costs identified as neutropenia-related were divided into 6 mutually exclusive categories including inpatient hospitalization, outpatient hospital/clinic, physician services, G-CSF therapy, home health care, and diagnostic testing. Inpatient, outpatient, physician services, and home health care costs were identified directly using primary or secondary ICD-9-CM diagnosis codes of 288.xx. Diagnostic testing costs were identified by the presence of both of the following on an administrative claim: (a) primary or secondary ICD-9-CM diagnosis code of 288.xx and (b) Current Procedural Terminology (CPT) code for specific laboratory services related to infection (Appendix 1). Costs for G-CSF were identified using only HCPCS codes (Appendix 1). Inpatient, physician services, and outpatient records were identified from the Medicare Provider Analysis and Review (MEDPAR), carrier claims, and outpatient claims files, respectively. To avoid double counting, costs for G-CSF and diagnostic testing were excluded from the physician services category if there was a diagnosis code for neutropenia appearing on these claims. Costs unrelated to neutropenia were estimated using all Medicare claims identified as unrelated to neutropenia.
Costs were calculated for each component by summing all Medicare payments, primary insurer payments, and patient neutropenia associated with chemotherapy, patients were excluded if they had claims for diseases of white blood cells (primary or secondary International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnosis code 288.xx) within 6 months prior to initiation of chemotherapy.
Finally, patients were included only if they were diagnosed with Stage IIIB or Stage IV NSCLC. Information pertaining to cancer stage was available in SEER and defined according to the third edition of the American Joint Committee on Cancer Staging Manual. 18 Stage IIIA and IIIB NSCLC were differentiated using extent of disease variables in SEER (Appendix 2).

Identification of the First-Line Chemotherapy Period
Data pertaining to the length of chemotherapy were not available in the SEER-Medicare database. Therefore, algorithms developed by the authors, based on their clinical expertise, were used to define treatment duration. First-line chemotherapy was defined as the initial regimen administered. The date on the earliest claim for chemotherapy was assumed to be the start date of firstline therapy. If a second first-line agent was administered within 8 days of the first administration, we considered this second administration to be combination first-line therapy. It was also assumed that if the same first-line agents were reintroduced after a time delay of any length (e.g., 8 weeks or more), this reintroduction was an extension of first-line treatment.
A switch to second-line therapy was assumed to have occurred only if a new agent not given during the first-line regimen was administered. The date on the first claim indicating a switch to a second-line agent was used to define the start of second-line therapy. The day prior to the switch was defined as the end of first-line treatment. If a switch to second-line therapy did not occur, then first-line therapy was assumed to end 30 days following administration of the last first-line agent. The study algorithm was not designed to identify chemotherapy regimens consisting of more than 2 agents because triplet therapy was not considered a standard of care in NSCLC during the study period (1998 through 2002). However, some patients who were prescribed triplet therapy with targeted agents may have been included in the sample.

Identification of Afebrile Neutropenia, Febrile Neutropenia, and No Neutropenia Groups
Each patient was categorized into 1 of 3 mutually exclusive categories: no neutropenia, febrile neutropenia, or afebrile neutropenia. Neutropenia was defined in the Medicare claims during receipt of first-line chemotherapy using primary or secondary ICD-9-CM diagnosis codes (288.xx, diseases of the white blood cells). An analysis of the frequency distribution of 288.xx codes used to identify patients with neutropenia revealed that more than 90% were for neutropenia (ICD-9-CM 288.0). Because it was assumed that claims for unspecified disease of white blood cells (ICD-9-CM 288.9) were for the treatment of neutropenia, these claims were also used to identify neutropenic patients. copayments and deductibles on the relevant claims occurring during first-line therapy. All costs were adjusted to 2005 U.S. dollars using the medical care services component of the Consumer Price Index (CPI).
Neutropenia-related health care utilization and costs were assessed from the date on the earliest Medicare claim for neutropenia through the end of first-line chemotherapy. Costs for health care unrelated to neutropenia were assessed from the start date through the end date of first-line chemotherapy. Total all-cause health care costs were calculated as the sum of neutropeniarelated and non-neutropenia-related costs.

Data Analyses
Baseline demographic and clinical characteristics including age, cancer stage at diagnosis, race, geographic region, NSCLC histology, Charlson comorbidity index, 20 type of chemotherapy regimen, and survival were assessed descriptively in order to identify characteristics that might affect health care utilization and costs. Median survival time, defined as the number of months from the start of first-line chemotherapy until death, was estimated using the Kaplan-Meier method. Survival times were censored (time to death was unknown) if patients were still alive as of their last day of follow-up care in the Medicare claims. Survival curves for the 3 cohorts were compared using the log-rank test. Group comparisons of patient characteristic and medical utilization study measures were made using 2-sided Pearson chi-square and t-test statistics for categorical and continuous measures, respectively. The no neutropenia group was used as the reference category. Where noted in the results, statistical testing was also used for comparisons between afebrile and febrile neutropenia groups.
Measures of health care utilization were summarized using descriptive statistics. Mean length-of-stay (LOS) was calculated by dividing the total number of inpatient care days summed across all patients in each study group by the total number of patients in each group. Confidence intervals (CI) for cost parameters were derived by using nonparametric bootstrap resampling and the percentile method. 21 We re-sampled with replacement from the study population to create 1,000 random samples. All estimates of neutropenia-related and total costs were repeated for each sample. CIs were derived from the sample distribution of costs from the 1,000 study replicates at the 2.5% and 97.5% quantiles. Total neutropenia-related costs were compared across afebrile and febrile neutropenia groups using a 2-sided t-test statistic.
Total all-cause health care costs were analyzed by the type of first-line chemotherapy received to determine if the relationship between costs and neutropenia was consistent across different regimens. Group comparisons of all-cause health care costs were made using 2-sided t-test statistics. The no neutropenia group was used as the reference category. For each of the 3 patient groups, costs were calculated per month of follow-up to account for differences in the length of first-line chemotherapy. Per patient per month (PPPM) costs were estimated by dividing (a) the per patient mean total all-cause health care costs for each patient group through all months of first-line chemotherapy by (b) the per patient mean number of months that each subgroup was treated with first-line chemotherapy. PPPM costs were calculated similarly for neutropenia-related costs and costs unrelated to neutropenia. We conducted a sensitivity analysis that limited neutropenia-related costs to health care claims containing a primary ICD-9-CM diagnosis code indicating neutropenia (288. xx). This was a stricter assumption over the main analysis that considered claims with either a primary or secondary code of 288.xx as related to neutropenia.
Statistical significance was evaluated at alpha = 0.05. SAS, version 9.1 (SAS Institute Inc., Cary, NC) was used for all analyses.

Sample Selection
From an initial sample of 72,571 patients with a primary diagnosis of NSCLC between 1998 and 2002, 5,138 met all study inclusion criteria ( Figure 1). A total of 3,190 patients did not have neutropenia during first-line chemotherapy, whereas 23.9% (n = 1,228) had at least 1 Medicare claim indicating a diagnosis of neutropenia. Among those with neutropenia, 740 were categorized as having afebrile neutropenia during receipt of first-line chemotherapy, and the remaining 488 were classified as having febrile neutropenia (14.4% and 9.5% of the entire study sample, respectively). Only 4% of cases were censored. Table 1 displays patient demographic and clinical characteristics by study group. Groups were comparable with respect to stage at diagnosis, race, geographic region, Charlson comorbidity index, and NSCLC histology. Patients with neutropenia were slightly older than patients without neutropenia (mean standard deviation [SD] ages in years 73.8 [5.2], 73.9 [5.2], and 73.4 [5.1] years for patients with afebrile, febrile, and no neutropenia, respectively, P = 0.048 afebrile vs. no neutropenia, P = 0.028 febrile vs. no neutropenia). The first-line chemotherapy regimens used by patients with afebrile and febrile neutropenia differed from those used by patients without neutropenia (P < 0.001 for both comparisons). The duration of first-line chemotherapy was longer for patients with afebrile neutropenia and febrile neutropenia than for patients without neutropenia (mean [SD] months 5.5 [7.0], 4.5 [4.8], and 3.6 [4.9], respectively, P < 0.001 for both comparisons). Estimated survival was longer for patients with afebrile neutropenia (median 8.1 months) versus those without neutropenia (median 6.3 months, P < 0.001).

Medical Resource Use During First-Line Chemotherapy
Data on medical resource use during first-line chemotherapy are reported in Table 2. Nearly three-quarters (72.3%) of febrile neutropenia patients were hospitalized as a result of neutropenia, and by design (i.e., the assumption that all hospital stays with a primary or secondary diagnosis of neutropenia represent febrile neutropenia), no patients were hospitalized for afebrile neutropenia. The number of physician visits related to neutropenia was similar among those with afebrile neutropenia and febrile neutropenia (mean [SD] 5.8 [8.8] and 6.3 [15.9] visits, respectively, P = 0.480). Throughout the period defined as first-line chemotherapy, the percentages of patients treated with filgrastim were higher for the afebrile neutropenia and febrile neutropenia groups than for the no neutropenia group (58.1%, 36.9%, and 3.2%, respectively, P < 0.001 for both comparisons).
The analyses of health care unrelated to neutropenia produced similar results. Patients with afebrile neutropenia or febrile neutropenia had more physician visits unrelated to neutropenia than did patients without neutropenia ( [18.4], respectively, P < 0.001 both comparisons). During first-line chemotherapy, patients with febrile neutropenia stayed in a hospice on average 0.6 days longer compared with patients in the without-neutropenia group (P = 0.041). Patients with afebrile neutropenia were more likely than those without neutropenia to be hospitalized for reasons unrelated to neutropenia (51.1% vs. 42.9%, respectively, P < 0.001), and LOS (inpatient days) for hospitalizations not related to neutropenia were higher among afebrile neutropenia patients compared with the no neutropenia group (mean [SD] days 3.5 [6.1] and 2.6 [4.7], respectively, P < 0.001). However, when LOS was measured per month of first-line chemotherapy, other inpatient LOS was comparable across study groups (0.6, 0.6, and 0.7 days for afebrile, febrile, and no neutropenia patients, respectively, data not shown).
As a sensitivity analysis, we considered Medicare claims

Characteristics of NSCLC Patients With Versus Without Neutropenia
than costs in the no neutropenia group. In patients receiving vinorelbine and gemcitabine combination therapy, the t-test showed that mean costs for patients with afebrile neutropenia were significantly higher than for patients without neutropenia. The validity of this t-test conclusion may be questionable since the 95% confidence intervals derived by nonparametric bootstrap resampling show that the difference in mean costs in the afebrile neutropenia and no neutropenia groups was not statistically significant. This result was similarly observed in the comparison of mean costs in febrile neutropenia and no neutropenia groups among patients receiving taxane monotherapy. The incremental differences in total costs between patients with febrile neutropenia and no neutropenia ranged from $8,384 to $23,339 for patients receiving taxane monotherapy and vinorelbine and gemcitabine combination therapy, respectively. The differences in total costs between patients with afebrile neutropenia and no neutropenia ranged from $8,853 to $17,959 for those receiving vinorelbine monotherapy and vinorelbine and platinum combination therapy, respectively.

All-Cause Health Care Costs During First-Line Chemotherapy
Mean all-cause per patient health care costs during first-line chemotherapy for each of the 3 study groups, in total and by specific first-line regimen received, are reported in Table 3. Total mean costs were higher for patients with febrile neutropenia ($37,694, SD = $26,078, 95% CI = $35,570-$40,110) and afebrile neutropenia ($34,204, SD = $26,317, 95% CI = $32,280-$36,165) than for those without neutropenia ($22,200, SD = $19,805, 95% CI = $21,559-$22,787, P < 0.001 for both comparisons). This relationship was observed across all regimen types. However, among patients receiving taxane monotherapy, total mean costs in the afebrile neutropenia group were not significantly higher patients with neutropenia and to assess health care use and costs related to the diagnosis during first-line chemotherapy.

Neutropenia-Related Costs in Patients Treated with First-Line Chemotherapy for Advanced Non-Small Cell Lung Cancer
Neutropenia-related costs were identified directly from the Medicare claims using ICD-9-CM diagnosis, procedure, and HCPCS codes. A cohort of patients without neutropenia was used to examine the association of neutropenia with treatment outcomes and costs. In contrast to previous studies examining costs and outcomes related to neutropenia, we compared treatment costs among patients with both afebrile and febrile neutropenia with treatment costs among patients without neutropenia.
Our analyses indicate that for elderly patients undergoing firstline chemotherapy for NSCLC, neutropenia and, in particular, febrile neutropenia are associated with additional health care costs attributable to increased use of medical services. The medical costs related to neutropenia observed during first-line chemotherapy were almost 4 times as high for patients with febrile neutropenia than for those with afebrile neutropenia ($12,148 vs. $3,099, P < 0.001). Among patients with febrile neutropenia, inpatient hospitalization made up approximately 63% of total neutropenia-related costs. For patients with afebrile neutropenia,

Mean Costs Per Month of First-Line Chemotherapy
Mean PPPM neutropenia-related, non-neutropenia, and total costs are shown in Figure 3. Monthly costs are presented to account for differences in the length of first-line chemotherapy observed among the different subgroups. Neutropenia-related costs were almost 5 times higher for febrile neutropenia versus the afebrile neutropenia subgroup ($2,700 vs. $563, difference = $2,137). A comparison of total monthly costs shows that there were also additional non−neutropenia-related treatment costs in patients with febrile neutropenia ($5,677), in afebrile neutropenia ($5,655), and no neutropenia ($6,146). Costs related to neutropenia for febrile neutropenic patients accounted for 32.2% of total costs during first-line chemotherapy compared with only 9.1% for afebrile neutropenia.

■■ Discussion
We used data from the SEER-Medicare linked database to estimate direct medical costs related to neutropenia in patients diagnosed with Stage IIIB or Stage IV NSCLC from 1998 through 2002. Medicare administrative claims were used to identify   neutropenia. 13,14 A 2008 article by Weycker et al. demonstrates that estimates based solely on complications resulting in hospitalization may be underestimating costs by as much as 40% by ignoring important follow-up care occurring after hospital discharge (i.e., increased physician monitoring, laboratory tests, antibiotics, and G-CSF therapy). 16 Weycker et al. found that hospitalizations accounted for approximately 60% of total neutropenia costs. This result was similar to the current study finding that hospitalizations represent nearly 63% of neutropenia-related costs in NSCLC patients with febrile neutropenia. the largest cost driver of neutropenia-related costs was physician services, which was expected since increased physician monitoring and antibiotic prophylaxis are often standards of care for patients at an increased risk of infection. PPPM health care costs unrelated to neutropenia were similar in the 3 study groups (afebrile neutropenia $5,655; febrile neutropenia $5,677; no neutropenia $6,146).

Comparison with Published Literature
Many studies analyzing the costs associated with neutropenia focus only on inpatient care related to the treatment of febrile a portion of patients with febrile neutropenia could have been misclassified in our analysis as having afebrile neutropenia. Because only low-risk patients would have been treated with oral antibiotics, the febrile neutropenia group in our study might be limited mostly to higher-risk, or more severe, patients in whom oral antibiotics would not be appropriate. This limitation might lead to an overstatement of the costs of febrile neutropenia relative to afebrile neutropenia.

Neutropenia-Related Costs in Patients Treated with First-Line Chemotherapy for Advanced Non-Small Cell Lung Cancer
Second, we relied on ICD-9-CM diagnosis codes to identify patients with neutropenia. Classification of febrile neutropenia was based on the assumption that either an inpatient record with a neutropenia diagnosis (in either the primary or secondary diagnosis field) or evidence of receipt of intravenous or intramuscular antibiotics following the initial neutropenia event indicated an episode of febrile neutropenia. Because it was beyond the scope of this study to perform confirmatory audits of individual patient medical records, the accuracy of using diagnosis codes to identify febrile neutropenia is unknown.
Third, we defined neutropenia-related costs using claims with a primary or secondary diagnosis of neutropenia. One potential limitation of this approach is that it is often difficult to identify all costs related to the treatment of a specific condition using an administrative database. For example, medical care utilization that is higher as a result of a disease, but cannot be identified using diagnosis or procedure codes, will not be included in disease specific estimates. To examine the impact of this limitation, we calculated PPPM health care costs unrelated to neutropenia for afebrile neutropenia ($5,655), febrile neutropenia ($5,677), and no neutropenia groups ($6,146). PPPM health care costs unrelated to neutropenia were lower in patients with afebrile and febrile neutropenia than for those without neutropenia. Therefore, using diagnosis codes to identify neutropenia-related costs should not bias cost estimates downward due to the exclusion of health care costs that are not disease specific (e.g., cannot be identified using diagnosis or procedure codes) but higher as a result of the complication. Another potential limitation of using primary or secondary diagnosis codes is that costs for neutropenia could have been overstated. To explore this limitation further we performed a sensitivity analysis restricting the definition of neutropenia-related costs to claims with a primary diagnosis of neutropenia. Using this more restrictive definition, neutropeniarelated costs during first-line chemotherapy were much lower than in our primary analyses, only $796 and $2,273 for patients with afebrile and febrile neutropenia, respectively. This suggests that our results are highly sensitive to the definition of neutropenia.
Fourth, Medicare claims are primarily used for administrative, not clinical, purposes in obtaining reimbursement for services provided to Medicare-eligible patients. Retrospective analyses of Medicare claims data, therefore, are subject to potential diagnostic and procedural coding inaccuracies, incomplete data, and may not be generalizable to non-Medicare beneficiaries. The Our inpatient cost estimates for patients with febrile neutropenia were comparable to those of previous studies, which reported costs in the range of $7,100 to $19,100 per neutropenia-related hospitalization despite differences in study designs and patient populations. [13][14][15][16] We report estimates that are towards the lower end of the range because of our definition of febrile neutropenia. As in previous studies, patients were defined as febrile neutropenic if they had an inpatient record indicating neutropenia. However, we also included patients who were treated solely on an outpatient basis with evidence of receipt of intravenous or intramuscular antibiotics. The lower estimates we report may be attributable to the lower cost of outpatient versus inpatient care.

Limitations
The first study limitation arises from Medicare coverage restrictions. During the study period, Medicare did not cover most oral prescription medications including those used to treat pain and infection. These medications, which often play an important role in the treatment of cancer, were not included in our estimates. This lack of information about oral antibiotic use means that study population included only Medicare eligible patients aged 65 years or older. Thus, cost and utilization results may not be representative of younger populations that may have different outcomes. 22 Other limitations include the potential for bias in group comparisons because of unmeasured confounders in this observational research. However, all measured baseline patient characteristics except for age and chemotherapy regimen were similar in patients with neutropenia versus those without neutropenia. In addition, although this study did not identify patients with more than 2 therapies, some patients who were prescribed triplet therapy with targeted agents could have been included in the sample. Patients who are administered triplet therapy with conventional and targeted agents may be at a higher risk for neutropenia

■■ Conclusion
Treatment with myelosuppressive chemotherapy is a standard treatment approach in Stage IIIB or Stage IV NSCLC. Although clinical trials have demonstrated a significant survival benefit in patients receiving platinum-based regimens versus supportive care alone, chemotherapy is also associated with various complications, including neutropenia. Neutropenia is a major adverse event that places patients at an increased risk of infection and subsequent morbidity and mortality. The descriptive findings presented here show that patients who develop afebrile or febrile neutropenia incur higher health care costs than patients who do not. The results may be useful in estimating the economic benefits associated with avoiding or reducing both types of neutropenia or in health-economic evaluations comparing specific chemotherapy regimens.